Journal
CHEMISTRY & BIOLOGY
Volume 8, Issue 3, Pages 277-287Publisher
CURRENT BIOLOGY LTD
DOI: 10.1016/S1074-5521(01)00006-0
Keywords
estrogen receptor; hormone specificity; receptor specificity reengineering
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Funding
- NCI NIH HHS [5R37 CA18119] Funding Source: Medline
- NCRR NIH HHS [RR 01575] Funding Source: Medline
- NIDDK NIH HHS [5R37 DK15556] Funding Source: Medline
- NIGMS NIH HHS [5T32 GM07283, GM 27019] Funding Source: Medline
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Background: The specificity of hormone action arises from complementary steric and electronic interactions between a hormonal ligand and its cognate receptor. An analysis of such key ligand-receptor contact sites, often delineated by mutational mapping and X-ray crystallographic studies, can suggest ways in which hormone-receptor specificity might be altered. Results: We have altered the hormonal specificity of the estrogen receptor alpha (ER) by making 'coordinated' changes in the A-ring of the ligand estradiol and in the A-ring binding subpocket of ER. These changes were designed to maintain a favorable interaction when both E and ER are changed, but to disfavor interaction when only E or ER is changed. We have evaluated several of these altered ligand and receptor pairs in quantitative ligand binding and reporter gene assays. Conclusions: In best cases, the new interaction is sufficiently favorable and orthogonal so as to represent the creation of a new hormone specificity, which might be useful in the regulation of transgene activity. (C) 2001 Elsevier Science Ltd. All rights reserved.
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